In the UK the annual referral rate for depression is around 300-400 per 10.sup.5 population of whom 10-15% require hospitalisation. At present the most effective and safe treatment for severe depression involves electroconvulsive therapy (ECT) where the patient receives a series of controlled electric shocks. However such treatment understandably engenders an atavistic fear and apprehension in many patients. It also has undesirable side-effects, notably disturbance of memory.
ECT is also expensive and time-consuming to administer, requiring the presence of specialist doctors such as psychiatrists and anaesthetists. As an alternative to ECT, drug therapy provides a more acceptable treatment for the patient but at the present time such therapy has not displaced ECT as the optimal treatment in severe cases because it is not always effective. There is therefore a need for new drugs for the treatment of depression, especially drugs having new modes of action mimicking ECT.
The mode of action of ECT remains unknown but in recent years much has been learnt about the biological effects of electroconvulsive shock (ECS) in animals. In particular; repeated ECS, given in ways closely mimicking those used to administer ECT clinically, elicits in rodents changes in monoamine functions.
These include: increased 5-HT-mediated behaviour, increased dopaminergic behaviour and depressed beta-adrenoceptor binding and sensitivity of the coupled adenylate cyclase. The last is also seen following chronic treatment with a number of antidepressant drugs.
The effects of repeated ECS are presumably a response or adaptation to the acute effects of the seizures. Among these acute effects are a marked change in the release, synthesis and level of gamma aminobutyric acid (GABA) in the brain.--see Green A. R. et al, British J. Pharmacol., 92, 5-11 and 13-18 (1987) and Bowdler et al, ibid, 76: 291-298 (1982).
GABA is one of the most widespread and abundant transmitters in the mammalian central nervous system and plays a major role in the control of brain excitability. It is similarly implicated in the benzodiazepine-mediated relief of anxiety. Recently evidence has come to light which suggests that GABA transmission may also be involved in the therapeutic effects of some antidepressant treatments. In particular, new compounds designed as GABA agonists (eg. fengabine and progabide) have been shown i n preliminary clinical trials to have antidepressant activity (vide infra). Taken together, these findings suggest that interventions directed specifically at GABA transmission may provide the basis of novel therapies for the treatment of affective disorders.
At present three GABA receptors have been identified in the central nervous system. These are (1) a GABA.sub.A -receptor known to be mainly postsynaptic and mediating inhibition of neuronal firing--see for example Stephenson, F. A. Biochem, J., 249 pp 21-32 (1988); (2) a GABA.sub.B receptor located presynaptically and mediating the inhibition of release of a number of neuro-transmitters; eq. noradrenaline and aspartec acid; but not GABA--see for example Bowery, N. G. et al, Nature, 283, 92-94 (1980); and (3) a GABA autoreceptor which modulates the release of GABA from neurones--see for example Mitchell, P. R., and Martin, I. L. Nature, 274 904-905 (1978); Arbilla, So Kanal, J. L. and Langer, S. Z. Eur. J. Pharmac., 57, 211-217 (1979) and Brennan M. J. W. et al, Molec. Pharmac., 19, 27-30 (1981).
The pharmacological importance of these receptors is currently a subject of investigation with a major part of the work involving the search for anticonvulsant drugs with a mode of action involving GABA.sub.A receptors. Two drugs acting on GABA receptors, progabide and fengabine, have also been shown to possess antidepressant effects in preliminary clinical trials--see P. L. Morselli et al, L.E.R.S. Vol 4 (1986) pp 119-126 and B. Scatton et al. Journal of Pharm. and Exp. Therapeutics., 241, 251-257 (1987 ). The latter workers showed that fengabine possessed a biochemical mode of action different from that of conventional antidepressants but that the mechanism whereby fengabine exerted its antidepressant actions was not yet clear. It was thought to derive from a GABAergic action, most likely at GABA.sub.A receptors.
In the case of progabide, Morselli et al also attributed the antidepressant effect to an increased GABAergic transmission.
In UK Patent No 2233558 evidence is provided that the antidepressant effect of progabide and fengabine is in fact due to their agonist action at the GABA autoreceptor. The GABA autoreceptor is capable of regulating the release of GABA from GABAergic neurons which means an agonist at the autoreceptor would decrease the GABA release hence decreasing GABA function ie. an action opposite to that of GABA.sub.A agonists. Previously the autoreceptor was believed to have the same pharmacology as the GABA.sub.A site--see Molec. Pharm, 19, 27-30 (1981). We have found that the GABA autoreceptor has its own distinct pharmacology and that there are compounds having selective agonist activity at the GABA autoreceptor. These compounds have valuable medical uses.
There is also evidence that compounds acting at the benzodiazepine receptor as inverse agonists decrease (GABA function in the brain and thus increase acetylcholine transmission. In addition, probably as a consequence of these actions, they facilitate memory in animals and man (see Sarter. M. et al. Trends in Neuroscience, 11 13-17, 1988). Compounds acting selectively as GABA autoreceptor agonists are believed to have similar actions such as nootropic activity (eg increased vigilance and cognition) and are therefore useful in the treatment of cerebral insufficiency disorders and dementias.
Secondary or tertiary (N-heteroaryl)methylamines structurally related to certain of those of formula Ia of the present application are disclosed in the literature.
G. Ruckdeschel et al., in Pharmazie, 1976, 31(6) pages 374-381 describe benzylamines of formula ##STR2## wherein R.sup.1 can be butyl and also the compounds: (92) Benzyl NMe-Bu
(94) Pyrid-3-ylmethyl NH-Bu
The benzylamines of this publication are stated to have tuberculostatic activity. However on page 377 of this publication it is stated (in German):
"Methylation of N-butylbenzylamine to the tertiary compound 92 results in a loss of activity. The replacement of phenyl by pyridyl to give compound 94 results in reduction of activity". R W Brimblescombe et al., in Br. J. Pharmacol. 1964, 23, 43-54 disclose the following compounds (Table 2 on page 45): PA1 9. 3-indolyl-CH.sub.2 CH.sub.2 N-nC.sub.4 H.sub.9 PA1 10. 3-indolyl-CH.sub.2 CH.sub.2 N-(nC.sub.4 H.sub.9).sub.2
There is no disclosure of the pharmaceutical uses of or related to those of the present application.
EP Publication No 177078 (Duphar) discloses spasmolytically active tertiary amines of the formula ##STR3## wherein, among others, A can be a 5- or 6- membered heteroaromatic group containing 1 or 2 of the following heteroatoms: oxygen and/or nitrogen and/or sulphur, R.sup.1 -R.sup.3 can be hydrogen or alkyl or alkoxy, n can be O, X can be SO.sub.2, R.sup.6 can be alkylene of 3 carbon atoms, R.sup.5 can be lower alkyl,
R.sup.7 and R.sup.8 can be a 5- or 6- membered ring.